MECHANISM OF GLUCOSE-INDUCED BIPHASIC INSULIN RELEASE - PHYSIOLOGICAL-ROLE OF ADENOSINE TRIPHOSPHATE-SENSITIVE K-INDEPENDENT GLUCOSE ACTION( CHANNEL)

The mechanism of glucose-induced biphasic insulin release by the B cel l was investigated using isolated rat pancreatic islets. In perifusion experiments, 16.7 mM glucose in combination with 25 mM K+ transformed the high K+-induced monophasic insulin release into a biphasic one in the presence of diazoxide (Dz), an ATP-sensitive K+ channel opener. I nclusion of Dz during the initial 6 min of glucose stimulation abolish ed the first phase, but was without effect on the second phase. In bat ch incubation experiments, fuels, including 16.7 mM glucose, 6 mM D-gl yceraldehyde, and 10 mM 2-ketoisocaproate, but not sulfonylurea, cause d time-dependent potentiation of the B cell so that the response to 25 mM K+, applied later, was increased in the fuel-primed islets. Inclus ion of Dz or lowering extracellular Ca2+ (to micromolar range) during the priming, which eliminates the initiation of insulin release, did n ot eradicate the potentiation. We conclude that high glucose closes AT P-sensitive K+ channels, leading to membrane depolarization, Ca2+ infl ux, and initiation of insulin release (first phase), and subsequently self-augments insulin release in an ATP-sensitive K+ channel-independe nt manner (second phase), acting at steps distal to cytosolic Ca2+ ele vation. The biphasic insulin release is thus generated by an interacti on of ATP-sensitive K+ channel-dependent and -independent glucose acti ons.